Tuesday, July 12, 2016

Editorial

Finding time to make the right decision: using frozen section to inform intra-operative management of suspicious ovarian masses

Jo Morrison, Toby Lasserson02 March 2016

Ovarian
cancer is the seventh most common cancer in women worldwide.[1] As with
many cancers, poor survival rates are largely attributable to the late
stage of presentation.[2] Women who present with a suspicious ovarian
mass without obvious disease outside of the ovary usually require
surgery for diagnosis and staging. Pre-operative biopsy is possible, but
it would risk dissemination of disease otherwise confined to the ovary.
Surgical removal of the mass is the only way to obtain a definitive
result by histological examination. A new Cochrane Review provides
crucial evidence on the accuracy of frozen section analysis, a rapid
diagnostic test that can inform management decisions of suspicious
ovarian mass during surgery.[3]

Normal histological diagnosis is a relatively slow process, requiring
multiple samples and steps for analysis. Known as a paraffin section,
tissue samples are fixed with formalin and embedded in paraffin before
being finely sliced, applied to slides, de-waxed and stained with dyes
and antibodies before being examined under a microscope.

Many women undergoing surgical staging may in fact be being exposed
to unnecessary risk. In a recent randomized controlled trial of
screening for ovarian cancer, only one in three women having surgery for
suspicious findings actually had ovarian cancer.[4] Identifying
cancerous tumours and staging them accurately helps to guide decisions
over further management, but should be balanced against avoiding
unnecessary surgical procedures.

Frozen section analysis allows for a 'quick and dirty' assessment of
the tumour. Samples are taken during the operation and snap frozen. They
are cut into slightly thicker slices in a refrigerated tissue slicer. A
result can be available within 20 to 30 minutes, meaning that decisions
over the requirement for further surgery can be made there and then.
However, speed comes at a price. Although results are available during
the operation, they may not be as accurate for borderline tumours. The
lack of fine structure preservation, the thicker slices, and limited
sampling of the tumour means that paraffin section is still a more
conclusive test.

While frozen section is not completely accurate, it is accurate
enough to help intraoperative decision-making and could reduce the
extent of surgery for a number of women ultimately found to have a
benign ovarian mass. Ratnavelu and co-workers estimated that if frozen
section was used to separate benign from borderline/malignant tumours,
280 women out of 1000 would be correctly diagnosed with a cancer and 635
would be correctly diagnosed without, and would not need, additional
procedures.[3] However, 85 women would have the diagnosis changed once
final paraffin section histology was available postoperatively; 75 women
would be incorrectly diagnosed with a cancer (false positive) and 10
women with a cancer would be missed on frozen section (false negative).
If frozen section was used to separate benign/borderline tumours from
cancer 261 women out of 1000 would have received a correct diagnosis of a
cancer and 706 women would be correctly diagnosed without a cancer.
Four women would be incorrectly diagnosed as having a cancer
intraoperatively and subsequently found not to have a cancer (false
positive), and 29 women with cancer would be missed (false negative).

Borderline tumours behave somewhere between a benign tumour and a
cancer: they can seed themselves within the abdominal cavity and grow on
the surface of other tissues, but they have not ‘learnt’ how to invade
other tissues. Borderline tumours recur in approximately 1 in 20 women,
often after a long time (sometimes over 20 years), but they do not
require chemotherapy. Surgical staging for borderline tumours does not
require removal of pelvic and para-aortic lymph nodes but ideally will
involve sampling of peritoneum and omentum.

Frozen section is unlikely to replace paraffin section for final
diagnosis, but this recent Cochrane Review demonstrates that it can
usefully differentiate benign tumours from those that need further
staging samples at the time of surgery.[3] Frozen section can be helpful
to tailor intra-operative management and can prevent many women
undergoing unnecessary procedures to remove lymph nodes. This reduces
the risk of perioperative complications and the long-term risk of
removing lymph nodes, including swelling of lower limbs and collections
of lymph fluid in the abdomen.

One driver for intraoperative staging is based on previous data that
suggested that women with early ovarian cancer who were inadequately
staged should be offered chemotherapy to reduce the risk of
recurrence.[5,6] These data were based on a five-year follow-up, but
data from 10-year follow-up has been incorporated into a recently
updated Cochrane Review.[7] Combined data from all women with
early-stage ovarian cancer shows a higher rate of survival with
postoperative chemotherapy. The number of women needed to treat for an
additional beneficial outcome (NNTB) to prevent one death within 10
years was approximately 13 (95% confidence interval 8 to 51). The review
authors also analysed 'deaths from ovarian cancer' at 10 years using
data from the ACTION and ICON1 trials.[5,8] This suggested that the
difference in deaths from ovarian cancer between optimally and
non-optimally staged patients was not statistically significant. It
should be noted that few of the women in the study had low-risk stage Ia
disease, so these data may not be applicable to this group, but the
analysis provides a controversial and intriguing challenge to a
long-held surgical 'certainty' that optimal staging with full
lymphadenectomy is vital and that women not optimally staged should be
offered additional surgery. It certainly adds weight to any technique,
such as frozen section, that can reduce the risk of complications and
unnecessary surgery for the majority of women who do not have even a
potential benefit.